Seizures are intermittent yet the underlying stimulus is constantly present, thus, seizure discharge must be set off by some initiating factor. The aim of this project is to assess the role of thyroid hormones in altering susceptibility of the brain to experimentally- induced seizures and to determine the site and mechanisms involved in this action. The project will study the role of thyroid hormones in brain development and aging from a neurophysiological and neurochemical standpoint. The hypothesis is that thyroid hormones alter seizure susceptibility through changes in cation and anion transport processes in neurons and/or glia by regulating the activities of the transport enzymes, Na+, K+-ATPase, Ca++, Mg++- ATPase, HCO3-ATPase, and carbonic anhydrase. A key role of thyroid hormone appears to be regulation of anion and cation transport via the mitochondrial enzyme, HCO3-ATPase, the cytosolic and membrane- bound enzyme, carbonic anhydrase, and Na+/K+-ATPase during early neuronal and/or glial development. HCO3-ATPase, in particular, appears to trigger the development of these two cell types. In the absence of adequate thyroid hormone during a critical period of maturation, the expressions of HCO3-ATPase as well as carbonic anhydrase and Na+/K+-ATPase activities in neurons and/or glia are delayed with resultant anatomical and biochemical alterations in brain characteristic of the hypothyroid state that cause increased seizure susceptibility. Our observations support this hypothesis. Thus, the activity of HCO3-ATPase exhibits a "spike-like" increase in activity at 3 and 12 postnatal days, responses that are attenuated by methimazole-induced hypothyroidism. These changes increase susceptibility to seizures. This hypothesis will be tested by biochemical and pharmacological approaches in vivo and in isolated glial and neuronal cell cultures. The activity of transport enzymes, the concentration of electrolytes, and the contents of DNA and protein will be determined in brain of rats and mice with hypothyroid or hyperthyroid states and the results correlated with thyroxine triiodothyronine and thyrotropin levels in plasma, iodothyronine 5'- and 5-monodeiodinase activities in brain and other tissues, and changes in brain excitability during maturation. The studies in mice will use genetic models of epilepsy that exhibit age-dependent alterations in thyroid status (DBA mice) and models of hypothyroidism (hyt/hyt mice). Since hypothyroidism in infants produce cretinism, understanding the processes by which this occurs is of great importance in the clinical control of this disease.